Methods of treating SARS-CoV-2 infections

ABSTRACT

The disclosure is directed to methods of using TUDCA, or a pharmaceutically acceptable salt thereof, or a derivative thereof, for the treatment of SARS-CoV-2 infections.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/921,071, filed Jul. 6, 2020, which claims the benefit of U.S.Provisional Application No. 63/024,541, filed May 14, 2020. Theentireties of the aforementioned applications are incorporated byreference herein.

TECHNICAL FIELD

The disclosure is directed to methods of using TUDCA, or a salt thereof,and derivatives thereof, for the treatment and prevention of SARS-CoV-2infections.

BACKGROUND

SARS-CoV-2 infections are a threat to public health. Treatments forSARS-CoV-2 infections, as well as treatments for COVID-19, the diseasecaused by the SARS-CoV-2 virus, are needed.

SUMMARY

The disclosure is directed to methods of treating a SARS-CoV-2 infectionin a subject in need of treatment comprising administering to thesubject a therapeutically effective amount of an agent that is TUDCA, ora pharmaceutically acceptable salt thereof, or a derivative thereof.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The disclosure may be more fully appreciated by reference to thefollowing description, including the following definitions and examples.Certain features of the disclosed compositions and methods which aredescribed herein in the context of separate aspects, may also beprovided in combination in a single aspect. Alternatively, variousfeatures of the disclosed compositions and methods that are, forbrevity, described in the context of a single aspect, may also beprovided separately or in any subcombination.

As used in the specification including the appended claims, the singularforms “a,” “an,” and “the” include the plural, and reference to aparticular numerical value includes at least that particular value,unless the context clearly dictates otherwise.

When a range of values is expressed, an exemplary embodiment includesfrom the one particular value and/or to the other particular value. Allranges are inclusive and combinable. Further, reference to values statedin ranges includes each and every value within that range. When valuesare expressed as approximations, by use of the preposition “about,” itwill be understood that the particular value forms another embodiment.The term “about” as used herein when referring to a measurable valuesuch as an amount, a temporal duration, and the like, is meant toencompass reasonable variations of the value, such as, for example, ±10%from the specified value. For example, the phrase “about 50%” caninclude ±10% of 50, or from 45% to 55%, inclusive of 50%.

It is to be appreciated that certain features of the disclosure whichare, for clarity, described herein in the context of separateembodiments, may also be provided in combination in a single embodiment.Conversely, various features of the disclosure that are, for brevity,described in the context of a single embodiment, may also be providedseparately or in any subcombination.

As used herein, whether by itself or in conjunction with another term orterms, “pharmaceutically acceptable” indicates that the designatedentity such as, for example, a pharmaceutically acceptable excipient, isgenerally chemically and/or physically compatible with other ingredientsin a composition, and/or is generally physiologically compatible withthe recipient thereof.

As used herein, whether by themselves or in conjunction with anotherterm or terms, “subject(s),” “individual(s),” and “patient(s)”, refer tomammals, including humans. The term human(s) refers to and includes, ahuman child, adolescent, or adult.

As used herein, whether by itself or in conjunction with another term orterms, it should be understood that the phrases “method of treating” and“method of treatment” may be used interchangeably with the phrase “foruse in the treatment of” a particular disease.

As used herein, whether by themselves or in conjunction with anotherterm or terms, “treats,” “treating,” “treated,” and “treatment,” referto and include ameliorative, palliative, and/or curative uses andresults, or any combination thereof. In other embodiments, the methodsdescribed herein can be used prophylactically, that is, preventatively.It should be understood that “prophylaxis” or a prophylactic use orresult do not refer to nor require absolute or total prevention (i.e., a100% preventative or protective use or result). As used herein,prophylaxis or a prophylactic (preventative) use or result refers touses and results in which administration of a compound or compositiondiminishes or reduces the severity of a particular condition, symptom,disorder, or disease described herein; diminishes or reduces thelikelihood of experiencing a particular condition, symptom, disorder, ordisease described herein; or delays the onset or relapse (reoccurrence)of a particular condition, symptom, disorder, or disease describedherein; or any combination of the foregoing.

As used herein, whether used alone or in conjunction with another termor terms, “therapeutic” and “therapeutically effective amount” refer toan amount of a compound or composition that (a) treats a particularcondition, symptom, disorder, or disease described herein; (b)attenuates, ameliorates, or eliminates one or more symptoms of aparticular condition, disorder, or disease described herein; (c) delaysthe onset or relapse (reoccurrence) of a particular condition, symptom,disorder, or disease described herein; (d) prevents the onset of aparticular condition, symptom, disorder, or disease described herein. Itshould be understood that the terms “therapeutic” and “therapeuticallyeffective” encompass any one of the aforementioned effects (a)-(d),either alone or in combination with any of the others (a)-(d).

As used herein, the term “alkyl”, by itself or as part of anothersubstituent, means, unless otherwise stated, a straight or branchedchain hydrocarbon radical having up to twelve carbon atoms. In someembodiments, the number of carbon atoms is designated (i.e., C₁-C₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. Alkyl groups may be optionallysubstituted as provided herein. In some embodiments, the alkyl group isa C₁-C₆ alkyl; in some embodiments, it is a C₁-C₄ alkyl.

The term “akenyl” as used herein refers to C₂-C₁₂ alkyl group thatcontains at least one carbon-carbon double bond. In some embodiments,the alkenyl group is optionally substituted. In some embodiments, thealkenyl group is a C₂-C₆ alkenyl.

The term “akynyl” as used herein refers to C₂-C₁₂ alkyl group thatcontains at least one carbon-carbon triple bond. In some embodiments,the alkenyl group is optionally substituted. In some embodiments, thealkynyl group is a C₂-C₆ alkynyl

The term “halo,” by itself or as part of another substituent, means afluorine, chlorine, bromine, or iodine atom.

The term “alkoxy” refers to those alkyl groups attached to the remainderof the molecule via an oxygen (O) atom.

The term “thioalkyl” refers to those alkyl groups attached to theremainder of the molecule via a thio (S, SO, SO₂) group.

The term “cycloalkyl” as used herein refers to a 3-12 membered cyclicalkyl group, and includes bridged and spirocycles (e.g., adamantine).Cycloalkyl groups may be fully saturated or partially unsaturated. Theterm “cycloalkyl” also includes multiple condensed ring systems (e.g.,ring systems comprising 2, 3 or 4 rings) wherein a single cycloalkylring (as defined above) can be condensed with one or more groupsselected from heterocycles, carbocycles, aryls, or heteroaryls to formthe multiple condensed ring system. Such multiple condensed ring systemsmay be optionally substituted with one or more (e.g., 1, 2, 3 or 4) oxogroups on the carbocycle or heterocycle portions of the multiplecondensed ring. The rings of the multiple condensed ring system can beconnected to each other via fused, spiro and bridged bonds when allowedby valency requirements. It is to be understood that the individualrings of the multiple condensed ring system may be connected in anyorder relative to one another. It is also to be understood that thepoint of attachment of a multiple condensed ring system (as definedabove for a cycloalkyl) can be at any position of the cycloalkylic ring.Examples of cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cycloheptyl, cyclohexyl, cycloheptyl, cyclooctyl, indenyl,bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, bicyclo[4.1.0]heptanyl,spiro[3.3]heptanyl, and spiro[3.4]octanyl. In some embodiments, thecycloalkyl group is a 3-7 membered cycloalkyl.

The term “cycloalkenyl” refers to a cycloalkyl moiety having one or moredouble bonds, for example, cyclohexenyl, cyclopropenyl, and the like.

The term “aryl” as used herein refers to a single, all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 12 carbon atoms. Aryl includes a phenyl radical. Arylalso includes multiple condensed ring systems (e.g., ring systemscomprising 2, 3 or 4 rings) having about 9 to 12 carbon atoms in whichat least one ring is aromatic and wherein the other rings may bearomatic or not aromatic. Such multiple condensed ring systems areoptionally substituted with one or more (e.g., 1, 2 or 3) oxo groups onany carbocycle portion of the multiple condensed ring system. The ringsof the multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the point of attachment of a multiple condensedring system, as defined above, can be at any position of the aromaticring. Non-limiting examples of aryl groups include, but are not limitedto, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and the like.

The term “aralkyl” refers to an aryl group attached to the remainder ofthe molecule through an alkyenyl group, for example, benzyl(phenyl-CH₂—)

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatoms are selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multiple condensed ring systems thathave at least one such aromatic ring, which multiple condensed ringsystems are further described below. Thus, “heteroaryl” includes singlearomatic rings of from about 1 to 6 carbon atoms and about 1-4heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Exemplary heteroaryl ring systemsinclude but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.“Heteroaryl” also includes multiple condensed ring systems (e.g., ringsystems comprising 2, 3 or 4 rings) wherein a heteroaryl group, asdefined above, is condensed with one or more rings selected fromheteroaryls (to form for example a naphthyridinyl such as1,8-naphthyridinyl), heterocycles, (to form for example a1,2,3,4-tetrahydronaphthyridinyl such as1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) toform the multiple condensed ring system. Thus, a heteroaryl (a singlearomatic ring or multiple condensed ring system) has about 1-20 carbonatoms and about 1-6 heteroatoms within the heteroaryl ring. A heteroaryl(a single aromatic ring or multiple condensed ring system) can also haveabout 5 to 12 or about 5 to 10 members within the heteroaryl ring.Multiple condensed ring systems may be optionally substituted with oneor more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycleportions of the condensed ring. The rings of a multiple condensed ringsystem can be connected to each other via fused, spiro and bridged bondswhen allowed by valency requirements. It is to be understood that theindividual rings of the multiple condensed ring system may be connectedin any order relative to one another. It is also to be understood thatthe point of attachment of a multiple condensed ring system (as definedabove for a heteroaryl) can be at any position of the heteroaryl ring.It is also to be understood that the point of attachment for aheteroaryl or heteroaryl multiple condensed ring system can be at anysuitable atom of the heteroaryl ring including a carbon atom and aheteroatom (e.g., a nitrogen). Exemplary heteroaryls include but are notlimited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl,pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl,benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl,5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl,thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one,triazolyl, 4,5,6,7-tetrahydro-1H-indazole and3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclo-penta[1,2-c]pyrazole. Inone embodiment the term “heteroaryl” refers to a single aromatic ringcontaining at least one heteroatom. For example, the term includes5-membered and 6-membered monocyclic aromatic rings that include one ormore heteroatoms. Non-limiting examples of heteroaryl include but arenot limited to pyridyl, furyl, thiazole, pyrimidine, oxazole, andthiadiazole.

The term “heterocyclyl” or “heterocycle” as used herein refers to asingle saturated or partially unsaturated ring that has at least oneatom other than carbon in the ring, wherein the atom is selected fromthe group consisting of oxygen, nitrogen and sulfur; the term alsoincludes multiple condensed ring systems that have at least one suchsaturated or partially unsaturated ring, which multiple condensed ringsystems are further described below. Thus, the term includes singlesaturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-memberedrings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatomsselected from the group consisting of oxygen, nitrogen and sulfur in thering. The ring may be substituted with one or more (e.g., 1, 2 or 3) oxogroups and the sulfur and nitrogen atoms may also be present in theiroxidized forms. Exemplary heterocycles include but are not limited toazetidinyl, tetrahydrofuranyl and piperidinyl. The term “heterocycle”also includes multiple condensed ring systems (e.g., ring systemscomprising 2, 3 or 4 rings) wherein a single heterocycle ring (asdefined above) can be condensed with one or more groups selected fromheterocycles (to form for example a 1,8-decahydronapthyridinyl),carbocycles (to form for example a decahydroquinolyl) and aryls to formthe multiple condensed ring system. Thus, a heterocycle (a singlesaturated or single partially unsaturated ring or multiple condensedring system) has about 2-20 carbon atoms and 1-6 heteroatoms within theheterocycle ring. Such multiple condensed ring systems may be optionallysubstituted with one or more (e.g., 1, 2, 3 or 4) oxo groups on thecarbocycle or heterocycle portions of the multiple condensed ring. Therings of the multiple condensed ring system can be connected to eachother via fused, spiro and bridged bonds when allowed by valencyrequirements. It is to be understood that the individual rings of themultiple condensed ring system may be connected in any order relative toone another. Accordingly, a heterocycle (a single saturated or singlepartially unsaturated ring or multiple condensed ring system) has about3-20 atoms including about 1-6 heteroatoms within the heterocycle ringsystem. It is also to be understood that the point of attachment of amultiple condensed ring system (as defined above for a heterocylyl) canbe at any position of the heterocyclic ring. It is also to be understoodthat the point of attachment for a heterocycle or heterocycle multiplecondensed ring system can be at any suitable atom of the heterocyclicring including a carbon atom and a heteroatom (e.g., a nitrogen). In oneembodiment the term heterocycle includes a C₂₋₂₀ heterocycle. In oneembodiment the term heterocycle includes a C₂₋₇ heterocycle. In oneembodiment the term heterocycle includes a C₂₋₅ heterocycle. In oneembodiment the term heterocycle includes a C₂₋₄ heterocycle. Exemplaryheterocycles include, but are not limited to aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl,tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4-tetrahydroquinolyl,benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl,spiro[cyclopropane-1,1′-isoindolinyl]-3′-one, isoindolinyl-1-one,2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-one N-methylpiperidine,imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, 1,4-dioxane,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, pyran,3-pyrroline, thiopyran, pyrone, tetrhydrothiophene, quinuclidine,tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane,(1s,4s)-2-azabicyclo[2.2.2]octane,(1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one. In oneembodiment the term “heterocycle” refers to a monocyclic, saturated orpartially unsaturated, 3-8 membered ring having at least one heteroatom.For example, the term includes a monocyclic, saturated or partiallyunsaturated, 4, 5, 6, or 7 membered ring having at least one heteroatom.Non-limiting examples of heterocycle include aziridine, azetidine,pyrrolidine, piperidine, piperidine, piperazine, oxirane, morpholine,and thiomorpholine. The term “9- or 10-membered heterobicycle” as usedherein refers to a partially unsaturated or aromatic fused bicyclic ringsystem having at least one heteroatom. For example, the term 9- or10-membered heterobicycle includes a bicyclic ring system having a benzoring fused to a 5-membered or 6-membered saturated, partiallyunsaturated, or aromatic ring that contains one or more heteroatoms.

“Pharmaceutically acceptable salt” refers to a salt of a compound of thedisclosure that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. In particular,such salts are non-toxic may be inorganic or organic acid addition saltsand base addition salts. Specifically, such salts include: (1) acidaddition salts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non-toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

A “solvate” refers to a physical association of a compound of thedisclosure with one or more solvent molecules.

As used herein, the term “isomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space, e.g., enantiomers,diastereomers, tautomers.

The disclosure is directed to methods of treating SARS-CoV-2 infections.According to these methods, a subject diagnosed with or suspected ofhaving a SARS-CoV-2 infection is administered an amount of an agent thatis tauroursodeoxycholic acid (TUDCA, also referred to herein as “TUDCAacid”), or a salt thereof, or derivative thereof that is therapeuticallyeffective in treating the SARS-CoV-2 infection.

Without wishing to be bound to any particular theory, it is believedthat TUDCA and its derivatives can treat SARS-CoV-2 infections byinhibiting viral replication. TUDCA and its derivatives are hydrophilicbile acids that can inhibit viral replication by disrupting the membranefunctions of a SARS-CoV-2 virus, disrupting the chaperone function ofheatshock proteins while providing alternative chaperone functionality,stabilizing a dysregulated endoplasmic reticulum, influencing mechanismsof protein folding, and/or facilitating the lipidation of cofactorsrequired for autophagy of virus-infected cells, and/or inhibiting theoverall availability or utility of cellular lipids for the purpose ofreplicating new viral particles.

TUDCA and its derivatives are water soluble. When administered, eitherparenterally, via inhalation, or orally, in the form of a dosage formincluding one or more pharmaceutically acceptable excipients, TUDCA andits derivatives are readily absorbed and distributed throughout thebody, including the central nervous system.

TUDCA is known in the art and has the following formula:

In preferred embodiments, the agent used in the methods of thedisclosure is TUDCA. In other embodiments, the agent used in the methodsof the disclosure is a pharmaceutically acceptable salt of TUDCA, forexample sodium TUDCA.

TUDCA derivatives are also within the scope of the disclosure. PreferredTUDCA derivatives are compounds that are not TUDCA (or apharmaceutically acceptable salt thereof) and that are of Formula I:

wherein

-   X is O or S;-   R¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,    C₁₋₆arlkyl, aryl, heteroaryl bound through a carbon atom, or    heterocycle bound through a carbon atom;-   R² is H, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₁₋₆arlkyl,    aryl, heteroaryl bound through a carbon atom, or heterocycle bound    through a carbon atom;-   R³ to R¹¹ are, independently, H, CN, OH, NO₂, N(R^(A))₂, halo,    C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,    C₁₋₆thioalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₁₋₆arlkyl, aryl,    heteroaryl, heterocycle, —OC(O)R^(A), —C(O)R^(A), C(O)OR^(A),    —OC(O)N(R^(A))₂, —C(O)N(R^(A))₂, —N(R^(A))C(O)OR^(A),    —N(R^(A))C(O)R^(A), —N(R^(A))C(O)N(R^(A))₂, —N(R^(A))S(O)₂R^(A),    —S(O)OR^(A), —S(O)₂OR^(A), —S(O)N(R^(A))₂, —S(O)₂N(R^(A))², or    PO₃(R^(A))₂;-   each R^(A) is, independently, H, OH, C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₁₋₆arlkyl, aryl, heteroaryl, or heterocycle;-   or a pharmaceutically acceptable salt, solvate, or isomer thereof.

According to the described methods, the agent, preferably TUDCA or apharmaceutically acceptable salt of TUDCA, is administered to thesubject. In some aspects, the agent is administered parenterally. Inother aspects, the agent is administered via inhalation. In preferredaspects, the agent is administered orally.

The amount of agent administered to the subject will be the amounteffective in treating the SARS-CoV-2 infection as described more fullyherein. For example, in some aspects, up to 5 g/day, up to 4 g/day, upto 3 g/day, up to 2 g/day, up to 1 g/day, or up to 0.5 g/day of theagent (preferably TUDCA or a pharmaceutically acceptable salt of TUDCA)will be administered to the subject. In other aspects, 0.5, 1, 1.5, 2,2.5, 3, 3.5, 4, or 4.5 g/day of the agent (preferably TUDCA or apharmaceutically acceptable salt of TUDCA) will be administered to thesubject.

In some aspects, the subject has been diagnosed with COVID-19. In otheraspects, the subject is suspected of having COVID-19. In other aspects,the subject intends to prevent the contracting of COVID-19.

In some aspects, the agent is administered prior to the subjectpresenting with a symptom of COVID-19. In other aspects, the agent isadministered to the subject after the subject has presented with asymptom of COVID-19.

In some aspects, the agent is administered to the subject prior to thedetection of any SARS-CoV-2 in a body fluid (e.g., blood, respiratoryfluid) of the subject. In other aspects, the agent is administered tothe subject after SARS-CoV-2 has been detected in a body fluid of thesubject.

In some aspects, the agent is administered to the subject for 1 day to90 days. In some aspects, the agent is administered to the subject for 1day to 60 days. In some aspects, the agent is administered to thesubject for 1 day to 30 days. In some aspects, agent is administered tothe subject for 1 day to 14 days. In some aspects, the agent isadministered to the subject for 1 day to 7 days. In some aspects, theagent is administered for 7 days. In some aspects, the agent isadministered for 14 days. In some aspects, the agent is administered for21 days. In some aspects, the agent is administered for 28 days. Whenused prophylactically, the agent is administered daily for as long asthe risk of infection persists.

The daily amount of the agent can be orally administered to the subjectin one dose or in divided doses throughout the day. In some aspects, theagent is administered once a day. In other aspects, the agent isadministered twice a day. In yet other aspects, the agent isadministered three times a day. Preferably, the agent is administeredonce per day or twice per day or three times per day.

In some aspects of the disclosure, the agent is administered to thesubject and the administration reduces the risk that the subject willbecome infected with SARS-CoV-2 after exposure to the SARS-CoV-2 virus.In some aspects of the disclosure, the agent is administered to thesubject and the administration reduces the risk that the subject willdevelop COVID-19 after exposure to the SARS-CoV-2 virus.

In some aspects, administration of an agent according to the disclosureresults in an improvement in one or more of the subject's SARS-CoV-2infection symptoms, as compared to the subject's baseline SARS-CoV-2infection symptoms. SARS-CoV-2 infection symptoms can vary, depending onthe particular subject. SARS-CoV-2 infection symptoms can include, e.g.,fever, rigors, decreased oxygen saturation, shortness of breath,difficulty breathing, fatigue, muscles aches, body aches, chest pain orpressure, headache, new loss of taste, new loss of smell, sore throat,congestion, nausea, vomiting, diarrhea, confusion, cough, and rash.

In some aspects of the disclosure, the administration of the agentresults in a reduction of the subject's fever. In other aspects, theadministration of the agent results in a reduction in rigors experiencedby the subject. In other aspects, administration of the agent results inan increase in the subject's oxygen saturation. In other aspects,administration of the agent results in a reduction in the subject'sfatigue. In other aspects, administration of the agent results in alessening of the frequency and/or severity of the subject's coughing. Inother aspects, administration of the agent results in a lessening of thesubject's rash.

In some aspects, the administration of the agent results in a reductionin the subject's viral load. Methods for determining viral load areknown in the art and include using PCR.

In some aspects, the administration of the agent results in animprovement in the subject's clinical status. Clinical status can bedetermined by those of skill in the art using the WHO Ordinal Scale forClinical Improvement, shown below.

Score Descriptor Patient State 0 No clinical or virologic evidence ofUninfected infection 1 No limitation of activities Ambulatory 2Limitation of activities Ambulatory 3 Hospitalized, no oxygen therapyHospitalized Mild Disease 4 Oxygen by mask or nasal prongs HospitalizedMild Disease 5 Non-invasive ventilation or high- Hospitalized SevereDisease flow oxygen 6 Intubation and mechanical Hospitalized SevereDisease ventilation 7 Ventilation + additional organ Hospitalized SevereDisease support - pressors, RRT, ECMO 8 Death Dead

In some aspects, the administration results in an improvement in thesubject's clinical status, as represented as a reduction in thesubject's WHO Ordinal Scale of 1 point. In some aspects, theadministration results in a reduction in the subject's WHO Ordinal Scaleof 2 points. In some aspects, the administration results in a reductionin the subject's WHO Ordinal Scale of 3 points. In some aspects, theadministration results in a reduction in the subject's WHO Ordinal Scaleof 4 points. In some aspects, the administration results in a reductionin the subject's WHO Ordinal Scale of 5 points. In some aspects, theadministration results in a reduction in the subject's WHO Ordinal Scaleof 6 points.

In some aspects, the agent can be used to inactivate SARS-CoV-2 presentin air so as to decrease the infectiousness of the SARS-CoV-2 in theair. In some aspects, the agent can be used to inactivate SARS-CoV-2present on surfaces so as to decrease the infectiousness of theSARS-CoV-2 on the surfaces.

The following examples are provided to illustrate some of the conceptsdescribed within this disclosure. While each example is considered toprovide specific individual embodiments of disclosure, none of theExamples should be considered to limit the more general embodimentsdescribed herein. In the following examples, efforts have been made toensure accuracy with respect to numbers used but some experimental errorand deviation should be accounted for.

EXAMPLES Example 1

The study is of TUDCA for treating a SARS-Co-V-2 infection. Followinginitial assessment of a subject, the subject's baseline viral load,viral infection symptoms, and clinical status will be documented.Subjects will be assigned to one of two treatment arms.

Arm A: TUDCA in addition to standard of care. TUDCA to be administeredas 500 mg capsules, b.i.d., for up to 90 days.

Arm B: placebo, in addition to standard of care.

Efficacy will be analyzed based on one or more endpoints including, forexample

-   -   change in clinical status using WHO Ordinal Scale    -   length of time to resolution of fever    -   length of time to normalization of oxygen saturation    -   overall survival    -   rate of non-elective mechanical ventilation    -   duration of mechanical ventilation    -   number of ICU days    -   any other criteria deemed relevant

Example 2

Thirteen rescue squad members servicing a New Jersey hospital facilitybetween March 2020 and May 2020 were provided with TUDCA gelatincapsules (500 mg, powder in capsule) and instructed to administer onecapsule, twice per day, for the duration of the COVID-19 epidemic.

Prior to initiating TUDCA administration, one member tested positive forSARS-CoV-2 and presented with COVID-19 symptoms. After twice dailyTUDCA, the member's health returned to normal.

None of the other twelve members have presented with COVID-19 symptoms,despite repeated exposure to COVID-19 patients over at least 3 months.

Example 3

A subject presenting with COVID-19 symptoms was instructed to administerone gelatin capsule of TUDCA (500 mg, powder in capsule), twice per day.After twice daily TUDCA administration, the subject's health returned tonormal.

Example 4

The study was to determine if commercial TUDCA (commercially available,manufactured in China), TUDCA acid (reagent grade, Sigma-Aldrich Inc.),or sodium TUDCA (reagent grade, Sigma-Aldrich Inc.) inhibit the growthof SARS-CoV-2 in vitro. USA-WA1/2020 strain of the virus was used,acquired from BEI Resourced. This was propagated in Vero E6 cells (ATCCCRL-1586); these cells were also used for the neutralization assay. VeroE6 cells were cultured in growth media consisting of Dulbecco's ModifiedEagle Medium/F12 (DMEM/F12) supplemented with 5% FBS, and PSN(penicillin, streptomycin, and neomycin).

The Vero E6 cells were plated on 96-well plates the day before the assayand were allowed to grow to ˜60% confluence. All three drugs werereconstituted with DMSO to a concentration of 100 mg/mL. That wasfurther diluted in DMEM/F12 to 5 mg/mL. TUDCA came out of solution thatthis point but the next 1:2 dilution was soluble and both were used inthe plate. A 1:2 serial dilution series was performed to examine finalconcentrations of 1.25, 0.625, 0.31, 0.156, 0.078, 0.039, and 0.02mg/mL. DMSO controls were used to account for DMSO concentrations at1.25, 0.625, 0.31, 0.156, 0.078, 0.039, and 0.02%. Dilutions werepre-incubated with virus for 60 minutes prior to addition to cells. Thiswas to allow drug to interact with virus prior to virus infection.Additionally, drug and virus were added to Vero cells simultaneously. 45minutes after virus addition, DMEM/F12+FBS was added to feed the cells.The assay was executed in five replicates for each condition. Test wellsreceived approximately 100 TCID50/well of SARS-CoV-2. Growth of the VeroE6 cells was observed and monitored for cytopathic effects (CPE)associated with successful virus replication. All wells were examined onDay 2 and Day 4 post-infection.

Cytotoxicity was seen in commercial TUDCA wells at 1.25 and 0.625 mg/mLfinal concentrations. Slowed cell growth was seen in 1.25 mg/mL of TUDCAacid and sodium TUDCA as well as corresponding DMSO controls (1.25%).Cytotoxicity was attributed to DMSO. Day 2 reads showed no CPE in 1.25mg/mL of TUDCA acid and sodium TUDCA for both viral preincubation andsimultaneous addition. Day 4 reads showed no CPE in 1.25 mg/mL of TUDCAacid and sodium TUDCA for simultaneous addition tests. Results aresummarized in Table 1 for 1.25 mg/mL concentrations and correspondingDMSO controls. Both TUDCA acid and sodium TUDCA had an EC50 of 0.98mg/ml as calculated by the Quest Graph™ EC50 Calculator from AATBioquest, Inc. All uninfected controls remained healthy and did notdisplay any CPE throughout the 4-day observation period. The back titerwas consistent with previous virus growth results.

TABLE 1 Results for Day 2 and Day 4 drugs at 1.25 mg/mL Day 2 Day 2 Day4 Day 4 CPE Cytotoxicity CPE Cytotoxicity Simultaneous TUDCA CPE inCytotoxicity CPE in Cytotoxicity addition 5/5 wells in 5/5 wells 5/5wells in 4/5 wells TUDCA acid No CPE Minimal No CPE No cytotoxicity in5/5 cytotoxicity in 4/5 in 5/5 wells wells in 5/5 wells wells SodiumTUDCA No CPE Minimal No CPE No in 5/5 cytotoxicity in 5/5 cytotoxicitywells in 5/5 wells wells in 5/5 wells DMSO CPE in Minimal CPE in Nocytotoxicity 5/5 wells cytotoxicity 5/5 wells in 5/5 wells in 5/5 wellsPre-Incubation TUDCA CPE in NA CPE in NA with Virus 5/5 wells 5/5 wellsTUDCA acid No CPE NA CPE in NA in 5/5 5/5 wells wells Sodium TUDCA NoCPE NA No CPE NA in 5/5 in 5/5 wells wells DMSO CPE in NA CPE in NA 5/5wells 5/5 wells

This experiment demonstrated that at 1.25 mg/mL, TUDCA acid and sodiumTUDCA inhibit SARS-CoV-2 infection of Vero cells when dosedsimultaneously with viral addition to cells. TUDCA acid and sodium TUDCAboth have a calculated EC50 of 0.98 mg/mL.

What is claimed:
 1. A method of treating COVID-19 in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of an agent that has the formula:

wherein: X is O or S; R¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, C₁₋₆arlkyl, aryl, heteroaryl bound through a carbonatom, or heterocycle bound through a carbon atom; R² is H, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₁₋₆arlkyl, aryl, heteroaryl boundthrough a carbon atom, or heterocycle bound through a carbon atom; R³ toR¹¹ are, independently, H, CN, OH, NO₂, N(R^(A))₂, halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆thioalkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₁₋₆arlkyl, aryl, heteroaryl,heterocycle, —OC(O)R^(A), —C(O)R^(A), C(O)OR^(A), —OC(O)N(R^(A))₂,—C(O)N(R^(A))₂, —N(R^(A))C(O)OR^(A), —N(R^(A))C(O)R^(A),—N(R^(A))C(O)N(R^(A))₂, —N(R^(A))S(O)₂R^(A), —S(O)OR^(A), —S(O)₂OR^(A),—S(O)N(R^(A))₂, —S(O)₂N(R^(A))², or PO₃(R^(A))₂; each R^(A) is,independently, H, OH, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆arlkyl, aryl,heteroaryl, or heterocycle; or a pharmaceutically acceptable salt,solvate, or isomer thereof; wherein said agent is nottauroursodeoxycholic acid (TUDCA).
 2. The method of claim 1, wherein theagent is administered orally.
 3. The method of claim 1, wherein theagent is administered parenterally.
 4. The method of claim 1, whereinthe agent is administered via inhalation.
 5. The method of claim 1,wherein the amount of the agent administered to the subject is up to 5g/day.
 6. The method of claim 1, wherein the agent is administered individed doses.
 7. The method of claim 1, wherein the administrationresults in a reduction in the subject's SARS-CoV-2 viral load.
 8. Themethod of claim 1, wherein the administration results in an improvementin one or more of the subject's viral infection symptoms.
 9. The methodof claim 1, wherein the administration results in an improvement in thesubject's clinical status.
 10. The method of claim 1, wherein thesubject has or is suspected of having COVID-19.
 11. The method of claim1, wherein the agent is administered after the subject is presenting asymptom of COVID-19.
 12. The method of claim 1, wherein the agent isadministered prior to the subject presenting a symptom of COVID-19. 13.A method of inactivating a SARS-CoV-2 virus comprising contacting thevirus with an effective amount of an agent that has the formula:

wherein: X is O or S; R¹ is H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, C₁₋₆arlkyl, aryl, heteroaryl bound through a carbonatom, or heterocycle bound through a carbon atom; R² is H, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₁₋₆arlkyl, aryl, heteroaryl boundthrough a carbon atom, or heterocycle bound through a carbon atom; R³ toR¹¹ are, independently, H, CN, OH, NO₂, N(R^(A))₂, halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆thioalkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, C₁₋₆arlkyl, aryl, heteroaryl,heterocycle, —OC(O)R^(A), —C(O)R^(A), C(O)OR^(A), —OC(O)N(R^(A))₂,—C(O)N(R^(A))₂, —N(R^(A))C(O)OR^(A), —N(R^(A))C(O)R^(A),—N(R^(A))C(O)N(R^(A))₂, —N(R^(A))S(O)₂R^(A), —S(O)OR^(A), —S(O)₂OR^(A),—S(O)N(R^(A))₂, —S(O)₂N(R^(A))², or PO₃(R^(A))₂; each R^(A) is,independently, H, OH, C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆arlkyl, aryl,heteroaryl, or heterocycle; or a pharmaceutically acceptable salt,solvate, or isomer thereof; wherein said agent is nottauroursodeoxycholic acid (TUDCA).
 14. The method of claim 13, whereinthe SARS-CoV-2 is airborne.
 15. The method of claim 13, wherein theSARS-CoV-2 is on a surface.